MMP Inhibitor Is Tested in Refractory Prostate Cancer

ASCO--An oral drug that blocks enzymes that appear to be fundamental
for tumor spread significantly slowed the rate of rise of PSA in men with
advanced hormone-refractory prostate cancer and may have the potential
to increase survival, Peter Boasberg, MD, reported at the ASCO meeting.

The agent, marimastat from British Biotech, is the first orally available
matrix metalloproteinase (MMP) inhibitor. The MMPs are a family of enzymes
that break down the basement membrane and the extracellular matrix.

Marimastat was designed to restrict cancer growth by several mechanisms.
"It prevents invasion of the surrounding local tissue, prevents migration
of cancer cells into lymphatics and blood vessels, and inhibits endothelial
cell recruitment," said Dr. Boasberg, of the John Wayne Cancer Center,
Santa Monica.

Because the agent is cytostatic rather than cytotoxic, it was not expected
to reduce tumor size but only to inhibit growth. Thus, the rate of rise
of PSA was chosen as a primary endpoint.

All of the 88 patients enrolled in this dose-ranging study had rapidly
progressing refractory prostate cancer (91% with stage IV disease). All
avoided hormonal therapy in the four weeks prior to initiation of the study,
as well as antiandrogens, to prevent a withdrawal response.

Overall, PSA rate of rise fell from a median of 53% to 29% during the
study. At higher marimastat dose levels (10 to 50 mg twice daily), a greater
proportion of patients had a decline (58% versus 34% at lower dose levels),
he said.

Among those who achieved a biologic effect (decrease in the PSA rate
of rise of 25% or more), median survival has not been reached at 400 days,
compared with 260 days median survival in those who did not achieve a biologic
effect. The vast majority of the responders are still receiving the drug
in a continuation study.

Marimastat was well tolerated, Dr. Boasberg said, with musculoskeletal
effects the dose-limiting toxicity. These symptoms subsided with a drug
holiday.

An audience member noted that PSA rate of rise has not been established
as a surrogate marker for prostate cancer progression and reduction in
PSA has not been shown to have an impact on outcome. But Dr. Boasberg countered
that "in this study, it did. We saw a substantial difference in survival
based on the velocity of the rise in PSA."